title: Protein kinase CK2 inhibition down modulates the NF-κB and STAT3 survival pathways, enhances the cellular proteotoxic stress and synergistically boosts the cytotoxic effect of bortezomib on multiple myeloma and mantle cell lymphoma cells.
abstract: CK2 is a pivotal pro-survival protein kinase in multiple myeloma that may likely impinge on bortezomib-regulated cellular pathways. In the present study, we investigated CK2 expression in multiple myeloma and mantle cell lymphoma, two bortezomib-responsive B cell tumors, as well as its involvement in bortezomib-induced cytotoxicity and signaling cascades potentially mediating bortezomib resistance. In both tumors, CK2 expression correlated with that of its activated targets NF-κB and STAT3 transcription factors. Bortezomib-induced proliferation arrest and apoptosis were significantly amplified by the simultaneous inhibition of CK2 with two inhibitors (CX-4945 and K27) in multiple myeloma and mantle cell lymphoma cell lines, in a model of multiple myeloma bone marrow microenvironment and in cells isolated from patients. CK2 inhibition empowered bortezomib-triggered mitochondrial-dependent cell death. Phosphorylation of NF-κB p65 on Ser529 (a CK2 target site) and rise of the levels of the endoplasmic reticulum stress kinase/endoribonuclease Ire1α were markedly reduced upon CK2 inhibition, as were STAT3 phospho Ser727 levels. On the contrary, CK2 inhibition increased phospho Ser51 eIF2α levels and enhanced the bortezomib-dependent accumulation of poly-ubiquitylated proteins and of the proteotoxic stress-associated chaperone Hsp70. Our data suggest that CK2 over expression in multiple myeloma and mantle cell lymphoma cells might sustain survival signaling cascades and can antagonize bortezomib-induced apoptosis at different levels. CK2 inhibitors could be useful in bortezomib-based combination therapies.
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Branch, University of Padova, Padova, Italy ; Myeloma and Lymphoma Pathobiology Laboratory, Hematologic Malignancies Unit, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Manni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Brancalion
authors.forename: Elisa
authors.initials: E
authors.lastname: Mandato
authors.forename: Laura Quotti
authors.initials: LQ
authors.lastname: Tubi
authors.forename: Anna
authors.initials: A
authors.lastname: Colpo
authors.forename: Marco
authors.initials: M
authors.lastname: Pizzi
authors.forename: Rocco
authors.initials: R
authors.lastname: Cappellesso
authors.forename: Fortunato
authors.initials: F
authors.lastname: Zaffino
authors.forename: Speranza Antonia
authors.initials: SA
authors.lastname: Di Maggio
authors.forename: Anna
authors.initials: A
authors.lastname: Cabrelle
authors.forename: Filippo
authors.initials: F
authors.lastname: Marino
authors.forename: Renato
authors.initials: R
authors.lastname: Zambello
authors.forename: Livio
authors.initials: L
authors.lastname: Trentin
authors.forename: Fausto
authors.initials: F
authors.lastname: Adami
authors.forename: Carmela
authors.initials: C
authors.lastname: Gurrieri
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.forename: Francesco
authors.initials: F
authors.lastname: Piazza
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015153:Blotting, Western; D001897:Boronic Acids / Q000378:metabolism / Q000494:pharmacology*; D000069286:Bortezomib; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000188:drug therapy*; D016328:NF-kappa B / Q000378:metabolism*; D009287:Naphthyridines / Q000494:pharmacology; D010619:Phenazines; D011719:Pyrazines / Q000378:metabolism / Q000494:pharmacology*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D001897:Boronic Acids; D017931:DNA Primers; D016328:NF-kappa B; D009287:Naphthyridines; D010619:Phenazines; D011719:Pyrazines; D050796:STAT3 Transcription Factor; D000069286:Bortezomib; D000255:Adenosine Triphosphate; C555142:silmitasertib; D047390:Casein Kinase II